Animal cells and tissues have different radiation sensitivity. In mammals, including humans, the symptoms resulting from exposure to radiation manifest in two phases, an acute phase, which may be referred to as acute radiation disorder, or a late onset phase, which may be referred to as late onset disorder. The acute phase disorder arises from damage to the highly sensitive cells and tissues of the immune system, the gastrointestinal system, and the central nervous system. The clinical symptoms of acute disorder begin with a decrease in lymphocytes followed by, for example, alopecia and skin erythema. The clinical manifestations of chronic disorder may be in the form of increased incidence of certain cancers as well as non-cancer diseases and genetic alterations which appear to occur stochastically rather than being subject to a certain exposure threshold (Kamiya K et al., 2012, Nihon Rinsho 70(3):367-74).
Acute radiation syndrome, also referred to as acute radiation sickness (ARS) is an acute disorder caused by whole body irradiation from a high dose of penetrating radiation (e.g., greater than 1 gray, abbreviated “Gy”) during a short time period, typically over a period of minutes. In a human subject receiving high doses of radiation, both mature lymphocytes and bone marrow stem cells were severely damaged, causing profound depletion of granulocytes and natural killer cells, which together defend against microbial (or bacteria and viral) invasion. This damage to the immune system makes exposed subjects particularly vulnerable to death from active infections. In addition, cells responsible for innate immunity were activated and produced inflammatory proteins (Yamaoka M et al., 2004, Radiation Research 161:290-8; Effect of the immune system, Radiation Effect Research Foundation). Filgrastim, an agonist of granulocyte colony-stimulating factor (G-CSF) has been suggested as a treatment for ARS because GCSF can increase white blood cell production thereby possibly enhancing the response of the immune system to microbial infections. However, filgrastim has shown variable positive results in animal studies.
Immune cells are known to be vulnerable to radiation. Radiation triggers the changes and effects in the immune system as well as killing healthy cells after irradiation. Radiation induces apoptosis (programmed cell death) in mature natural killer cells (lymphocytes responsible for innate immunity) as well as T and B lymphoctes (white blood cells responsible for adaptive immunity). Radiation also induces lethal damage to the bone marrow stem cell precursors of monocytes, and granulocytes and natural killer (NK) cells. In individuals receiving high doses of radiation, for example, atomic bomb survivors, both mature lymphocytes and bone marrow stem cells were severely damaged, causing profound depletion of granulocytes and natural killer cells (Park B et al. 2014 Int J Mol Sci 15(1):917-943).
Under certain conditions, radiation treatment can also enhance the immune response. For example, radiation exposure can provide a source of antigen that is well-suited for cross presentation by the host antigen-presenting cells (i.e., dendritic cells) which in turn can induce an antigen-specific immune response during radiotherapy of cancer patients. In addition, other immunopotentiating properties of radiation therapy have been observed, for example its influence on the tumor microenvironment which includes enhancing cell trafficking to tumor sites. At present, the numerous distinct and overlapping cell signaling pathways induced by radiation exposure and their interaction is not entirely understood. But understanding a fuller understanding of these pathways is needed for developing more efficient radiotherapies with beneficial, rather than pathological, biological and immunological consequences (Park B et al. 2014 Int J Mol Sci 15(1):917-943; Eriksson D et al., 2010 Tumor Biol. 31:363-72; Verheij Met al. 2000 Cell Tissue Res 301:133-142).
Several cytokines are believed play a role in innate defenses against ionizing radiation. For example, some studies indicated that mice can be protected from death by administration of interleukin-1 (IL-1), tumor necrosis factor (TNF), stem cell factor (SCF), IL-12, or basic fibroblast growth factor (bFGF), within 18-24 hrs prior to whole body irradiation (Heslet L et al. 2012 Int K Gen Med 5:105-115; Neta R 1997 Stem cells 15:87-94). However, none of these has been developed for use in humans as radioprotective agents.
The Toll-like receptor 5 (TLR5) agonist CBLB502 (entolimod) was granted orphan drug status for reducing the risk of death following a potentially lethal dose of total body irradiation (TBI) when administered during or after exposure to radiation. Entolimod induces nuclear factor NF-κB signaling, activating the innate immune response (Burdelya L et al., 2008 Science 320(5873) 226-230). A single intramuscular injection of entolimod given after a lethal dose of total body irradiation increased survival in tests on non-human primates (NHPs). Entolimod mitigates radiation damage to hematopoietic and gastrointestinal tissues and promotes tissue regeneration. It also accelerates the recovery of peripheral blood cellularity and hemoglobin content, and improves the morphological recovery of hematopoietic and lymphoid organs including bone marrow, thymus, spleen and mesenteric lymph nodes. In addition, treatment with entolimod increased circulating levels of the cytokines G-CSF, IL-6, IL-8 and IL-10 in the peripheral blood. (Krivokrysenko V et al. 2015 PLoS One 10(9): e0135388; Krivokrysenko V et al. 2012 J Pharmacol Exp Ther 343(2)). See also WO 2016/109002.
There remains a need for additional safe and effective therapeutic agents for the treatment and prevention of radiation induced cell and tissue damage and for the treatment and prevention of radiation-induced diseases, disorders, and conditions.